Popescu Recipient of NINDS Research Program Award

By Dirk Hoffman

Gabriela K. Popescu, PhD, a professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences, continues to lead research on fast neurotransmitter brain receptors focused on gaining the basic knowledge necessary for the design of more effective therapeutic approaches for many neuropsychiatric conditions.

The grants, which were first awarded by the National Institutes of Health in 2017,  support the overall research programs of NINDS-funded investigators for up to eight years, at a maximum level of $750,000 direct costs per year — providing greater funding stability to allow investigators increased freedom to embark upon research that breaks new ground or extends previous discoveries in new directions.

The R35 RPA is highly competitive — eligibility is limited to investigators who currently have at least one active NINDS R01 grant and have been continuously funded by NINDS for at least the past five years. Popescu has received continuous NINDS funding since 2006.

The grant, whose funding cycle is expected to begin in 2023, is titled “Molecular Physiology of NMDA Receptor.” The research seeks to describe how NMDA (N-methyl-D glutamate) receptors operate and how their activity can be controlled with drugs for therapeutic gain.

NMDA receptors are the most abundant calcium-passing neurotransmitter receptors in brain and spinal cord; they initiate and control synaptic development and plasticity; and their dysfunction or dysregulation causes pernicious neuropsychiatric disorders.

“In the central nervous system, the activation of NMDA receptors produces electrical currents that are essential for brain functions such as cognition, learning and memory,” Popescu says.

“Excess activation causes pathological cellular loss in stroke, brain and spinal cord injuries, and age-related diseases such as Alzheimer’s and Parkinson’s. In this project we will study how the internal parts of the receptor move during receptor activation and how prospective drugs or clinically identified mutations alter these motions.”

Popescu says despite intense research over the past 50 years, the enormous potential of NMDA receptor-targeted therapies remains untapped.

“In our grant application, we argued that this failure to reign in these receptors with pharmacotherapies is rooted in the lack of basic understanding of how they work,” she says.

Over the past 20 years, Popescu’s research — supported by the National Institutes of Health and the American Heart Association — has developed three novel approaches that can now be leveraged together in this new longer-term research program to delineate the operation of NMDA receptors:

• from a past project, the researchers learned to observe the tiny (picoampere) electrical signals produced by single receptors and to organize them into a sequence of events that can tell us how fast or how slow the receptor works in a given environment
• through a collaboration developed over the years with Wenjun Zheng, PhD, professor of  physics in UB’s College of Arts and Sciences, the researchers learned what movements have to happen at an atomic scale within the receptor molecule for the normal electrical signals to occur
• the researchers now know how to measure not only how much electricity these receptors produce, but how much of that electrical signal is carried specifically by calcium, which is the real culprit in causing neuronal death upon NMDA receptor overactivity

“With these new methods we can look ‘under the hood’ to understand how the different modules that make these receptors work together to produce electrical signals, and how drugs can attach to these modules to change the intensity and the quality of the signals produced,” Popescu says.

The overall objective of the research is to describe the NMDA receptor activation, which consists of stochastic transitions between closed, open and desensitized states, with a level of detail that integrates atomic structural information obtained from static receptor conformations with coarse-grained and atomistic molecular dynamic simulations, she adds.

The structural results will be tested with kinetic and thermodynamic measurements of NMDA receptor current output.

Specific aims of the study are:

• identifying atomic structures representative for each of the three main functional states (closed, open, desensitized) and how these structures interconvert
  
• delineating key atomic interactions that control these changes in structure
  
• describing how the dynamic distribution of receptors across this conformational landscape controls the patterns of depolarization and calcium influx produced by NMDA receptors
  

“We will then use the resulting integrated mechanism to examine how disease-related mutations and small-molecule modulators affect the conformational dynamics of receptors and how they alter the NMDA receptor current,” Popescu says.

“The project will produce a congruent model that can be used to develop small-molecule modulators targeted to specific receptor conformations that would reduce calcium flux independently of excitatory action and will guide therapeutic approaches for patients with dysfunctional NMDA receptor genetic variants.”

The R35 RPA also espouses principles that are very important to Popescu — diversity and inclusion.

The program aims to advance the scientific and technical merit of projects through expanded inclusivity and requires a holistic description of how projects will support this aim.

“I was enthusiastic to apply for this R35 award, not only for the stability it would provide my research program and the ability to integrate several research projects, but also for freeing time from administrative tasks that will allow me to engage more vigorously with outreach activities,” Popescu says.

To maintain a diverse team over the long term, Popescu says she invests a considerable portion of her time doing outreach — speaking about her lab’s research to undergraduate and graduate students at scientific meetings, as an invited speaker at other universities, and with the public.

“I endeavor to attract, recruit and retain a diverse group of individuals who share genuine excitement for science and a passion for understanding how the brain works,” she says. “It has been important for me to develop a team that included, from the start, individuals across several dimensions of diversity including in interests and experiences, career stage and background.”

“Mentoring is integral to my mission as a scientist. It is both a guiding principle and a deeply personal commitment,” Popescu adds. “I believe that strong, productive research programs rely on strong and productive teams and my role as group leader is to help develop, guide and support the intellectual growth and maturation of all team members.”